Amines containing the king system



Patented Dec. 12, 1950 AMINES CONTAINING THE RING SYSTEM OF LYSERGICACID OR DIHYDROLYSER- GIG ACID AND A PROCESS SAME OF MAKING ArthurStoll, Albert Hofmann, and Franz Troxler,

Basel, Switzerland, assignors to Sandoz Limited, Basel, Switzerland NoDrawing. Application December 16, 1947, Se-

rial No. 792,096. In Switzerland December 20,

8 Claims. 1 It has been found that amines possessing either the ringsystem of lysergic acid and corresponding to the general formulaCH15N2NH2, or possessing the ring system of dihydrolysergic acid andcorresponding to the general formula cisHrzNaNl-lz can be obtained byheating the azides of the lysergic or dihydrolysergic acid isomers inaqueous acid solution. In the new compounds, the

carboxyl group of'the lysergic acid isomers of the formulaC15H15N2.COOH, and of the dihydrolysergic acid isomers of the formula isreplaced by a primary amino group.

The nomenclature of these new amino-derivatives can be derived fromergoline, the parent body of this class of compound (W. A. Jacobs and R.G. Gould, J. Biol. Chem. 120, 141 (1937)). In the case ofdihydrolysergic acid and its two stereoisomers, dihydro-isolysergic acid(I) and dihydroisolysergic acid (II) (A. Stoll, A. Hofmann and Th.Petrzilka, Helv. Chim. Acta 29, 635

8 7 COOH I II III I II III Ergoline Dihydrolysergic acid(i-Methyl-R-amino-ergoline Dihydro isolysergic acid (I) Dihydroisolysergio acid (H) (i-Methyl-S-aminc-isoergoline (I)6-Methyl-8-ami.no-isoergoline (II) The formulae of the lysergic acidisomers and their corresponding amino degradation products difier fromthe above-named ergoline derivatives only by an additional carbon-carbondouble bond,

the position of which is not yet certain (L. C. Craig, Th. Shedlovsky,R. G. Gould, Jr., and W. A. Jacobs, J. Biol. Chem. 125, 289 (1938)).Lysergic acid can therefore also be referred to as6-methyl-B-carboxy-ergolene and. the corresponding amine as6-methyl-S-amino-ergolene. In the case of isolysergic acid, thedesignation would be 6-methyl-8-carboxy-isoergolene and for thecorresponding amine, 6-methyl-8 aminoisoergolene.

The process of the present invention consists in adding dilute boilingacid, e. g. 0.2-N. hydrochloric acid, to the crystalline salts of theazides of the. lysergic or dihydrolysergic acid isomers and continuingboiling until the evolution of nitrogen and carbon dioxide is complete.This takes 1 to 2 minutes. Alternatively, the acid solution of the azidechlorhydrate, which results from the preparation of the azide from thehydrazide (A, Stoll and A. I-Iofmann, Helv. Chim. Acta, 26, 953 (1943)may be heated without previous isolation of the crystalline azidechlorhydrate and boiled until the evolution of gas ceases.

From the degradation, especially of lysergic acid or isolysergic acid, adark coloured reaction solution results, from which the crude amine maybe precipitated by addition of sodium carbonate or alkali, or, as it isusually more advantageous, it may be extracted, after basification, withchloroform or with another suitable solvent.

It is well-known that degradation of lysergic acid or isolysergic acidderivatives always produces a mixture of the two isomeric forms (A.Stoll and A. Hofmann, Helv. Chim. Acta 26, 953 (1943)). Thus, startingfrom lysergic acid or from isolysergic acid, both isomeric amines areinvariably obtained, although there is a strong quantitativepredominance of the amine with the lysergic acid structure, i. e.6-methyl-8-aminoergolene, in the first case, and of the isomeric6-methyl-8-amino-isoerg0lene in the second case. The mixture of the twoisomeric amines may be separated by fractional crystallization of thebases or of suitable salts or by means of chromatographic adsorptionanalysis.

No isomerisation takes place on degradation of the azides of thehydrogenated acids, and the corresponding homogeneous amino-derivativesare always obtained.

The new amines have well-defined crystalline forms and, in a pure state,are almost colorless di-acidic bases. They are slightly to moderatelysoluble in Water, but with inorganic or organic acids they formwell-defined crystalline salts which are more or less readily soluble inwater depending upon the nature of the acid radical. With ferricchloride in glacial acetic acid and concentrated sulphuric acid theystill give Kellers blue colour reaction, this reaction beingcharacteristical for the natural ergot alkaloids.

A few characteristic properties of the new compounds which are valuabletherapeutics and intermediates for the preparationof therapeutics aresummarised in the following table.

Table Amino-derivatives obtained by degradation of lysergic acid,isolysergic acid, dihydrolysergic acid, dihydro-isolysergic acid (I) anddyhydrosoluble in water and readily soluble in dilute aqueous acids.

Required: 0:75.26, H=7.16, N=1'7.5'7%. Found: 0:75.37, H=7.09, N=l7.62%.

Example 2 Preparation of 6-methyl-S-amino-isoergolene:

1.0 part by weight of freshly prepared crystalline isolysergic acidazide hydrochloride is treated with 50 parts by volume of boiling 0.1-N.sulphuric acid. Boiling is continued until the evolution of gas ceases(1-2 minutes). After cooling, the solution is made alkaline with causticsoda and isolysergic acid (II). 15

M. P. [a]

D devggllp (pyridine) Typical crystalline form 0. Deg1ees v or6-methyl-8-amino-isocrgolene, GHHiJNz. 198 +249 From alcohol, in heavyprisms and polyhcdra. dinethyl-8-aminoergoline, GlH19N3. 243 -117 Fromdethylacetate, in heavy, oblique truncate prisms.6=inethyl-8-amino'isoergoliiie (I), C 275-280 66 Frlonl 1 iinethanol, inelongated, hexagonal 19 a. 7 h ea e S. .fi-methyl-8-amino-isoergoline(II), 01 203 +29 From ethylacetatc, in heavy, upright trunmNa; catedprisms.

T e present invent on may now be illustrated, but not limited, by thefollowing examples.

Example 1 Preparation of 6methyl-8-amino-ergolene:

2.0 parts by weight of freshly prepared, crystalline lysergic acida'zide hydrochloride are treated with 100 parts by volume of boiling6.2-1 l. hydr'ochlo'ric acid and gently boiled for a further twominutes. During this time the azide hydrochloride .passesqinto solutionwith violent gaseous evolution. After cooling, the light brown solutionis made alkaline with sodium bicarbon ate and extracted with a totalvolume of 500 parts by vol. of chloroform. The chloroform solution isdried with sodium sulphate and evapora ed to dryness, leaving a residueweighing approxiinate'ly 1.3 parts by weight, correspending to a yieldof 90% of the theoretical.

The mixture of crude amino derivatives is subjected to chromatographicadsorption analysis. The substance is adsorbed from chloroform solutionon 500 parts by weight or aluminium oxide. On developing thechromatogram with chloroform containing 0.5% of alcohol, a few oilyimpurities first pass into the filtrate. Then follows the main fraction,approximately 0.6 part by weight of pure 6-methyl 8-amirioergolene, [a]=+9 l (pyridine). The succeeding fractions exhibit a higher specificrotation (+1so to +220') and represent a mixture of'6-inthyl-8aminoergolene and its isomer which arises by rearrangement during thecourse of the degradation. 0.3part by weight of crude 6 niethyl8=amino-isoergolene is thus obtained. I v

Ihe 6-.inethyl 8 aminorg'olene is recrystallized from chloroform, givingelongated, octagonal plates containing one molecule of chloroform ofcrystallization and. melting at 246 C. (decomp). The solvent-freecompound melts at 252-25.: C. (decomp). The amine dissolves, at theboiling point, in 50 parts of chloroform, parts of alcohol or 300 partsof benzene. it is moderately the amine extracted with i000 parts byvolume o f benzene. The aqueous phase is extracted twice more using 200parts by volume of the same solvent each time. The combined benzeneextracts are dried with sodium sulphate and evaporated to dryness invacuo, leaving a residue of 0.6 part by weight of crude amine. Thecompound is purifieq by repeated recrystallization from a littleabsolute alcohol, the accompanying amine of the 'lysergic acid seriesremaining in solution. I

g The pure 6 methyl 8 amino isoergolene is difficultly soluble inbenzene, readily soluble in alcohol, and very readily soluble inmethanol. It crystallizes from two latter solvents .in clear, heavyprisms and polyhedra,

M. P. 198 C. (decomp).

iai =+24e (0:0.5 in pyridine) Empirical formula CisHi'iNi Required;C=75.26, H5716, N"'=17.5"7%. Fo'iihd: (3 75.48, H 725, N=17.78%;

Erample 3 Preparation of (imethyl 8-aminoergoline:

2.8 parts by weight of finely powdered dihydrolysergic acidazide-hydrochloride (A. Stoll, A. Hofmann and Th. Petrzilka, Helv. Chim.Acta 29, 650 (1946) are treated with parts by Volume of (Ll-N. boilinghydrochloric acid and boiled for a few minutes. On rapidly cooling thesolution and making alkaline with caustic soda, the amino-derivativeseparates out in a crystalline form. It is left to stand at 0 C. for onehour to ensure completion of crystallization, and then filtered off andwashed with water. Yield 1.8 parts by weight. A further-0.12 part byweight of amine may be recovered from the aqueous mother liquors byextraction with chloroform. The total yield of 1.92 parts by weightcorresponds to 94% of the theoretical.

The 6 methyl 8 aminoergoline crystallizes from ethyl acetate in large,oblique, truncated prisms, free from solvent of crystani'zation andmelting with decomposition at 243 0., it is soluble, at the boilingpoint in 100 parts of ethyl acetate, 200 parts of benzene, 25 parts ofacetone or 10 parts of methanol.

[a] =-117 (c=0.5 in pyridine) Empirical formula CisHisNsz Required::74.64, H=7.94, N=1'7.42%. Found: C=74.85, H=8.02, N=17.23%.

Example 4 Preparation of fi-methyl-B-amino-isoergoline (I):

0.33 part by weight of dihydro-isolysergic acid (I) azide hydrochloride(prepared according to A. Stoll, A. Hofmann and Th. Petrzilka, Helv.Chim. Acta 29, 649 (1946)) is treated with 50 parts by volume of boiling0.5-N. acetic acid and boiled for 2 minutes. The amino-derivative isextracted with chloroform from the cooled reaction mixture after makingalkaline with sodium carbonate. The chloroform solution is dried withsodium sulphate and concentrated in vacuo to 5 parts by volume, when 0.2part by weight of 6- methyl-8-amno-isoergoline (I), crystallizes out infine clusters of needles, the yield corresponding to 85% of thetheoretical. By recrystallization from methanol, the amineis obtained inelongated, hexagonal leaflets. It dissolves, at the boiling point, in150 parts of methanol or ethanol or in 200 parts of chloroform, andmelts indefinitely with decomposition at 275280 C.

[a] =-66- (0:02 in pyridine) Empirical formula CisHmNa:

Required: C=74.64, H=7.94, N=1'7.42%. Found: C=74.66, H=7.90, N=17.55%.

Example 5 Preparation of 6-methyl-8-amino-isoergoline (II) 0.765 part byweight of dihydro-isolysergic acid (II) hydrazide is dissolved in 27parts by volume of 0.1-N. hydrochloric acid, 27 parts by volume of0.1-N. sodium nitrite solution are added and 16 parts by volume of0.2-N. hydrochloric acid allowed to run in dropwise over 3 minutes at 0C. with good st rring. The mixture is left to stand at 0 C. for'2minutes to allow completion of the azide formation. The solution is thenheated rapidly to the boiling point over a naked flame and boiled untilthe evolut on of gas ceases, which takes about 3 minutes. The amine isextracted with chloroform from the cooled solution after making alkalinewith caustic soda. After drying the chloroform solution with sodiumsulphate and evaporation in vacuo, 0.535 part by weight of crude amineremains, corresponding to a yield of 82% of the theoretical.

On recrystallization of the 6-methvl-8-aminoisoergoline (II) fromvolumes of ethyl acetate, massive upright truncated prisms are obtained,which melt at 203 C. with decomposition. The amine is soluble at theboiling point in '70 parts of benzene or 100 parts of water. It is veryreadily soluble in methanol or ethanol.

[a] =-l29 (c=0.5 in pyridine) Empirical formula CH19N3:

Required: C=74.64, H='7.94, N=17.42%. Found: C=74.83, H=8.14, N=17.83%.

What we claim is:

1. A process for the manufacture of a heterocyclic amine of the ergoleneseries, which comprises the step of boiling in a dilute acid aqueoussolution an azide of the ergolene series of the formula C15H11N2CO-N3,wherein n represents one of the integers 15 and 17, until the evolutionof nitrogen and carbon dioxide has ceased.

2. A process for the manufacture of 6-methyl- 8-amino-ergolene, whichcomprises the step of boiling lysergic acid azide in a dilute aqueoussolution of hydrochloric acid until the evolution of nitrogen and carbondioxide has ceased.

3. A process for the manufacture of G-methyl- B-amino-isoergolene, whichcomprises the step of boiling isolysergic acid azide in a dilute aqueoussolution of sulfuric acid until the evolution of nitrogen and carbondioxide has ceased.

4. A process for the manufacture of G-methyl- 8-amino-ergoline, whichcomprises the step of boiling dihydrolysergic acid azide in a diluteaqueous solution of hydrochloric acid until the evolution of nitrogenand carbon dioxide has ceased.

5. The optically active amines containing a ring system selected fromthe group consisting of lysergic acid and dihydrolysergic acid, and theisomers thereof, corresponding to the general formula C15II71N2NH2, nrepresenting, in the general formula one of the integers 15 and 17,which amines are d acidic, salt-forming bases giving Kellers blue colorreaction and which are therapeutically useful compounds.

6. The G-methyl-S-aminoergolene of the formula C15H1'7N3 which is acrystalline compound melting with decomposition at 252-253" C., havingan optical rotation of [a] =-|96 (pyridine) and giving Kellers bluecolor reaction.

7. The 6-methyl-8-amino-isoergolene of the formula CISHI'INS which is acrystalline compound melting with decomposition at 198 0., having anoptical rotation of [a] =+249 (pyridine) and giving Kellers blue colorreaction.

8. The 6-methyl-8-aminoergoline of the formula C15H19N3 which is acrystalline compound melt ng with decomposition at 243 C. having anoptical rotation of [a] =117 (pyridine) and giving Kellers blue colorreaction.

ARTHUR STOLL. ALBERT HOFMANN. FRANZ TROXLER.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Num er Name Date 2,090,430 Stoll et a1 Aug. 1'7,1937 2,265,217 Stoll et a1 Dec. 9, 1941 OTHER REFERENCES Sidgwick,Organic Chemistry of Nitrogen (Oxford Univ. Press, 1937), DD. 374376.

Stoll et al., Helv. Chim. Acta, vol. 26, pp. 2070-2081 (1943).

Hofmann, Helv. Chim. Acta, vol. 30, pp. 44-51 (February 1947).

2. A PROCESS FOR THE MANUFACTURE OF 6-METHYL8-AMINO-ERGOLEN, WHICHCOMPRISES THE STEP OF BOILING LYSERGIC ACID AZIDE IN A DILUTE AQUEOUSSOLUTION OF HYDROCHLORIC ACID UNTIL THE EVOLUTION OF NITROGEN AND CARBONDIOXIDE HAS CEASED.